Abstract

Non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations initially respond to EGFR tyrosine kinase inhibitors (TKI) but ultimately develop resistance to these therapies. The most common mechanism of resistance is a second site gate-keeper mutation within exon 20 of EGFR (T790M), followed by MET and other receptor tyrosine kinase amplification/activation. We developed a covalent mutant-selective EGFR inhibitor, EGF816 that potently inhibits both activating EGFR mutations as well as the T790M resistance mutation while sparing wild-type EGFR. EGF816 demonstrated strong tumor regressions in several EGFR activating and resistant tumor models in vivo. These include H1975 (L858R; T790M), HCC827 (exon 19 del) and H3255 (L858R) that are representative of the relevant clinical settings. In all of the models EGF816 inhibited tumor growth in a dose dependent manner and achieved regressions of established tumors at well tolerated doses. In single dose studies, EGF816 showed sustained inhibition of pEGFR, consistent with the irreversible binding mechanism of EGF816. EGF816 also performs exceptionally well in long term dosing studies providing durable responses in the preclinical models. Together, this data indicates that EGF816 exhibits excellent anti-tumor activity in the relevant patient derived tumor cell lines at well tolerated doses and is expected to provide long term duration of responses compared to current EGFR TKI therapy in the clinic.